α-(aminoalkyl)-arylacetic acid derivatives

ABSTRACT

Novel α-aryl-α-(ω-aminoalkyl)-α-[hydroxy(aralkyl and cycloalkyl)]acetic acid derivatives and α-aryl-α-(ω-aminoalkyl)-α[alkanoyloxy(aralkyl and cycloalkyl)]acetic acid derivatives, such as N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, 2-(hydroxyphenylmethyl)-5-dimethylamino-2-phenylpentanenitrile, ethyl 2-(hydroxyphenylmethyl)-5-dimethylamino-2-phenylpentanoate, and N,N-dimethyl-2[(acetyloxy)phenylmethyl]-4-dimethylamino-2-phenylbutanamide, useful in the treatment of cardiovascular disease.

BACKGROUND OF THE INVENTION

This invention pertains to novel α-aryl-α-(ω-aminoalkyl)-α-[hydroxy(aralkyl and cycloalkyl)]acetic acid derivatives and α-aryl-α-(ω-aminoalkyl)-α-[alkanoyloxy(aralkyl and cycloalkyl)]acetic acid derivatives, useful in the treatment of cardiovascular disease.

Others have disclosed the synthesis of various α-aryl-α-(ω-aminoalkyl)-α-(aralkyl and cycloalkyl)acetic acid derivatives and one α-aryl-α -(ω-aminoalkyl)-[hydroxy (alkyl)]acetic acid derivative.

The synthesis of various α-(pyridyl)-α-(ω-aminoalkyl)-α-[aralkyl, cycloalkyl, alkyl and cycloalkyl(alkyl)]acetic acid derivatives, and measurements of their anti-arrhythmic activities, were reported by C. A. Bernhart et al in "Synthesis and Antiarrhythmic Activity of New [(Dialkylamino)alkyl]pyridylacetamides", J. Med. Chem. 26, 451-455 (1983). In U.S. Pat. No. 4,356,177, the synthesis of α-(pyridyl)-α-(ω-aminoalkyl)-α-[cycloalkyl, alkyl, alkenyl, alkynyl, and cycloalkyl (alkyl)]acetic acid derivatives, and, in some instances, measurement of their antiarrhythmic activities were disclosed.

N,N-Dimethyl-4-dimethylamino-2-(1-hydroxypropyl)-2-phenylbutyramide, was described by R. E. Stenseth and Frederich F. Blicke in "Cyclization of Basic Amide Hydrochlorides, A New Synthesis of Substituted Lactams", The Journal of Organic Chemistry 34, 3007-3010 (1969). No biological data was reported.

In addition, various ω-amino-2-phenyl-2-pyridylbutyramides and ω-amino-2-phenyl-2-pyridylvaleramides, as eurhythmic agents, and the corresponding nitriles were reported in Chemical Abstracts (1963), Column 12522, (which cites Belgium Pat. No. 617,730 and two United States application dates). In U.S. Pat. No. 3,225,054, 4-dipropylamino-2-aryl-2-pyridylalkanamides, as eurhythmic, anti-inflammatory and diuretic agents, and the corresponding nitriles, were described. The synthesis of α-benzyl-α-[2-(dimethylamino)ethyl]-2-pyridine acetamide was described in Chemical Abstracts 63, 18019b, but no biological activity was discussed. Phenylacetic acid esters substituted on the α-carbon with alkyls, alkenes, alkynes, aralkyls, aryls, cycloalkyls, and cycloalkenyls, as well as with (dialkylamino)alkyl and cycloaminoalkyl groups were described in Chemical Abstracts 70, 55926 g; some of these had antidepressant activity. British patent specification No. 771,814, "New Butyryl Amides and Processes for their Manufacture" disclosed disubstituted amides of α-phenyl-α-(2-pyridyl)-ω-(disubstituted-amino)-butyric acids as antihistaminic and antispasmodic agents.

BRIEF SUMMARY OF THE INVENTION

The compounds of the invention are those of formula (I): ##STR1## wherein R is hydrogen or lower alkanoyl;

R₁ and R₂ are independently hydrogen, lower alkyl, or

lower cycloalkyl, or R₁ and R₂ together with their adjacent

nitrogen atom form a heterocyclic ring containing 4 to 6 carbon atoms;

R₃ is phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or lower cycloalkyl;

Ar is phenyl, substituted phenyl, or 2-pyridyl;

X is CN, CO₂ R₄, or CONR₅ R₆ ;

R₄ is hydrogen or lower alkyl;

R₅ and R₆ are independently hydrogen or lower alkyl, or

R₅ and R₆ together with their adjacent nitrogen atom form a heterocyclic ring containing 4 to 6 carbon atoms; and

n is 2 or 3, including all enantiomers thereof and mixtures of enantiomers thereof.

Preferred compounds of the invention are the compounds of the invention provided:

(1) R₃ is not 3-pyridyl or 4-pyridyl;

(2) R₃ is not 2-pyridyl in a compound in which X is CONHCH₃, R is H, Ar is phenyl, and n is 2;

(3) R₃ is not 2-pyridyl in a compound in which X is CN, R is H, Ar is phenyl, and n is 3; and

(4) R₃ is not phenyl substituted with lower alkoxy in a compound in which X is CON(CH₃)₂, R is H, Ar is phenyl, and n is 3.

In subgeneric aspects of the invention, the compounds of the invention and the preferred compounds are defined as above except that R₃ is not cycloalkyl.

The invention also encompasses processes for the preparation of the compounds of the invention.

The invention is also a method of treating angina comprising the administration, to a mammal in need of such treatment, of either a compound of the invention or a compound of formula I in which R, R₁, R₂, Ar, X, R₄, R₅, R₆ and n are defined as for the compounds of the invention and R₃ is lower alkyl, including all enantiomers thereof and mixtures of enantiomers thereof.

The invention is also a method of treating an anti-arrhythmic condition comprising the administration, to a mammal in need of such treatment, of either a preferred compound of the invention or a compound of formula I in which R, R₁, R₂, Ar, X, R₄, R₅, R₆, and n are defined as for the compounds of the invention and R₃ is lower alkyl, including all enantiomers thereof and mixtures of enantiomers thereof.

DETAILED DESCRIPTION

The compounds of the invention are calcium antagonists and, as such, are useful in the treatment of angina in a mammal (e.g., humans). Furthermore, their calcium antagonist activity is likely to render the compounds of the invention useful in the treatment of hypertension and arrhythmia.

It has also been suggested that such activity will render compounds useful in the treatment of asthma, migraine and artherosclerosis. The calcium antagonist activity of the compounds of the invention can be demonstrated using the calcium receptor binding assay of R. J. Gould et al, Proceedings of the National Academy of Sciences, USA, 79, 3656-3660 (1982) to show a reversal of verapamil inhibition of 3H-nitrendipine binding.

The preferred compounds of this invention have antiarrhythmic activity in addition to activity against angina. The antiarrhythmic activity of a preferred compound can be demonstrated by the reversal of ouabain-induced arrhythmias in an anesthetized dog that has been prepared for recording systemic arterial blood pressure and lead II ECG. After a 30 minute stabilization period, a priming dose of 50 μg/kg (iv) ouabain is given. At 15 minute intervals additional increments of 10 μg/kg ouabain is given until either ventricular tachycardia or multifocal ectopic arrhythmias are obtained. The test compound is then administered at 10 mg/kg (iv) or less and the ECG is monitored for changes indicative of reversal of the arrhythmias. A compound is considered active if it causes a return to normal heart action.

An appropriate procedure for administering either a compound of the invention to a mammal suffering from angina, or a preferred compound of the invention to a mammal suffering from arrhythmia, is at a dose of about 0.1 to 100 mg/kg of body weight per day as a single dose, but preferably divided among two to four daily doses, and preferably orally, although the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed. The dosage may be varied, depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.

Compounds of formula I in which R, R₁, R₂, Ar, X, R₄, R₅, R₆, and n are defined as for the compounds of the invention and R₃ is lower alkyl, including all enantiomers thereof and mixtures of enantiomers thereof, have both calcium antagonist activity (and, as such, are useful in the treatment of angina) and antiarrhythmic activity. An appropriate means of administering these compounds to a mammal suffering from angina or arrhythmia is the same as that for administering a compound of the invention, or a preferred compound of the invention, to such a mammal.

Especially preferred compounds are those in which R is hydrogen or acetyl, R₁ and R₂ are either both CH₃, both isopropyl, or together with their adjacent N form piperidino; Ar is phenyl, and X is CN, CO₂ C₂ H₅, CONHCH₃, or CON(CH₃)₂. Of these, particularly preferred as anti-arrhythmics are N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, ethyl 2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenyl butanoate, N,N-dimethyl-2-(hydroxyphenylmethyl)-4-diisopropylamino-2-phenylbutanamide, N,N-dimethyl-2-(hydroxy phenylmethyl)-5-dimethylamino-2-phenylpentanamide, ethyl 2-(hydroxyphenylmethyl)-5-dimethylamino-2-phenylpentanoate, N,N-dimethyl-2-[hydroxy(4-methoxyphenyl)methyl]-4-dimethylamino-2-phenylbutanamide, N,N-dimethyl-2[(acetoxy)phenylmethyl]-4-dimethylamino-2-phenylbutanamide; N,N-dimethyl-2-[(acetyloxy)(4-methoxyphenyl)methyl]-4-dimethylamino-2-phenylbutanamide (also particularly preferred as a calcium antagonist), N,N-dimethyl-2-(hydroxyphenylmethyl-4-piperidino-2-phenyl butanamide, N,N-dimethyl-2-(hydroxyphenylmethyl)-5-diisopropylamino-2-phenylpentanamide, and N,N-dimethyl-2-(hydroxyphenylmethyl)-5-piperidino-2-phenylpentanamide.

Lower alkyl and lower alkoxy contain 1 to 4 carbon atoms. Lower alkanoyl contains two to four carbon atoms, including the carbon atom attached by a double bond to the alkanoyl moiety. Lower cycloalkyl groups contain 3 to 6 carbon atoms. A heterocyclic ring contains 4 to 6 carbon atoms, one or two nitrogen atoms, and either zero or one oxygen atoms; it is exemplified by pyrrolidine, piperidine, morpholine, piperazine, and 1H-hexahydroazepine. Substituted phenyl is phenyl that is either monosubstituted or disubstituted, and each substituent is selected from the group consisting of halogen (preferably chlorine or bromine), lower alkyl, lower alkoxy, amino, nitro, or hydroxy; substitution can occur at the ortho, meta, or para positions.

It will be recognized by those skilled in the art of organic chemistry that, because there are two assymetric carbon atoms in each compound, each compound of the invention can exist as either of two diastereoisomers (the threo diastereoisomer and the erythro diastereoisomer). Furthermore, each diastereoisomer has two enantiomeric forms, corresponding to its two optical enantiomers. Therefore, each compound of the invention can exist in any one of four enantiomeric forms.

Each claim to a compound includes its pharmaceutically acceptable acid addition salts. Acid addition salts include those derived from both organic and inorganic acids, such as, for example, acetic acid, maleic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like.

PREPARATION OF COMPOUNDS

The methods for synthesizing the compounds of this invention are summarized in Charts A and B below. The encircled letters identify each method as either Method A, B, C, D, F or G, and "hyds" stands for hydrolysis. In chart A, Z₁ is a suitable nitrogen protecting group and Z₂ is either R₂ or together withh Z₁ and the adjoining nitrogen forms a suitable nitrogen protecting group. Chart B illustrates the preferred methods for preparing the compounds described in that chart.

CHART A ##STR2## CHART B ##STR3## ABBREVIATIONS

For the sake of brevity, n-BuLi means n-butyl lithium, LDA means lithium diisopropylamide, THF means tetrahydrofuran, MeOH means methanol, EtOH means ethanol, EtOAc means ethyl acetate, Et₂ O means ethyl ether, RT means room temperature (about 23° C.), aq means aqueous, hr means hour(s), min means minute(s), mp means melting point, and bp means boiling point.

Temperatures are in degrees centigrade.

In discussions of chromatographic procedures, r_(f) refers to the ratio D₁ :D₂ where D₁ and D₂ are the average distances traveled along the chromatographic plate by the diastereoisomer and the solvent front, respectively, during the chromatographic process. The chromatographic procedure separates compounds into two diastereoisomers as one has a higher r_(f) value (the high r_(f) diastereoisomer) than the other (the low r_(f) diastereoisomer). The terms "high melting point diastereoisomer" and "low melting point diastereoisomer" of a given compound refer to the diastereoisomers with the higher and lower melting points, respectively.

Method A

In the case where R₁ and R₂ are other than hydrogen, derivatives of the formula (II) ##STR4## (wherein Ar, and X, and n, are as defined for the compounds of the invention) are available from the reaction of the corresponding alkanoic acid derivative ArCH₂ X (where Ar and X are as earlier defined) with a haloalkylamine Y(CH₂)_(n) NR₁ R₂ (where R₁ and R₂ are independently lower alkyl or lower cycloalkyl, or where R₁ and R₂ together with their adjacent nitrogen atom form a heterocyclic ring containing 4 to 6 carbon atoms, and where n is 2 or 3, and Y is halo), in the presence of a strong base such as sodium amide (NaNH₂) and an inert solvent, at temperatures of about 70° to 140° C. depending on the solvent used.

Method B

Where either R₁ or both R₁ and R₂ are hydrogen, ArCH₂ X is reacted with either Y(CH₂)_(n) NR₁ Z₁ or Y(CH₂)_(n) NZ₁ Z₂, (wherein Z₁ is a suitable nitrogen protecting group, and Z₂ is either R₂ or together with Z₁ and the adjoining N group forms a protecting group such as pthalimido, n is 2 or 3, and Y is halo). The resulting adduct is reacted with the aldehyde, R₃ CHO, to give the nitrogen-protected 2-(arylhydroxymethyl) derivatives, and the nitrogen-protecting groups are then removed by well-known methods to give the corresponding formula I compound where R is hydrogen and either R₁ or both R₁ and R₂ are hydrogen. Examples of suitable nitrogen-protecting groups are phthalimido, ethoxycarbonyl, benzyloxycarbonyl, and benzyl.

Method C

The formula II compounds where X is CO₂ R₄ are prepared from the formula II compounds, where X is CN by reacting the nitrile with an alcohol (R₄ OH) saturated with hydrogen chloride to form the imino-ether hydrochloride (at about 20 to 100° C. depending on the alcohol), which is then hydrolyzed with water at about 15°-40° C. and basified to give the corresponding ester.

Method D

The intermediate formula II compounds where X is CONH₂ can be prepared by acid hydrolysis of the corresponding formula II compound where X is CN according to Bernhart et al. [For example, with sulfuric acid at about 80° to 100° C.].

Method E

Formation of the formula II compounds where X is CONR₅ R₆, and R₅ or R₆ is lower alkyl, or R₅ and R₆ are both lower alkyl, are prepared by the procedures of Bernhardt et al and Stenseth et al. Formula II compounds where R₅ and R₆ together with their adjacent nitrogen atoms form a heterocyclic ring containing 4 to 6 carbon atoms are prepared according to Bernhardt et al and Stenseth et al.

Method F

The compounds of formula I wherein R is H can be conveniently prepared by contacting a compound of formula II (wherein Ar, X, n, R₁ and R₂ are as defined for the compounds of the invention) with an aldehyde R₃ CHO (wherein R₃ is as defined for the compounds of the invention) under nitrogen, in the presence of a strong base such as n-BulI or LDA and an inert solvent such as THF or ether, at a temperature of from about -70° to +20° C., preferably at about 0° C.; and (b) recovering from the resultant reaction mixture the corresponding formula I compound.

Method G

Compounds of formula I in which R is H can in turn be conveniently converted to formula I compounds wherein R is lower alkanoyl by contacting the compound recovered in step (b) of Method F with an anhydride (R)₂ O (wherein R is lower alkanoyl) under nitrogen, in a solvent such pyridine, at ambient temperature and recovering from the resultant reaction mixture the desired compound.

SINGLE POT PROCEDURE (METHOD A PLUS METHOD F)

Starting with the ArCH₂ X derivative, the formula I compounds wherein R is hydrogen and neither R₁ nor R₂ are hydrogen can also be prepared in a single pot procedure by a sequential reaction, at about -70° to +20° C., in which said derivative is first reacted with about one equivalent of a strong base such as n-BuLi or LDA (about two equivalents of a strong base in the case where X is CONHR₅) and about one equivalent of the haloalkylamine Y(CH₂)_(n) NR₁ R₂ (where R₁ and R₂ are alkyl or cycloalkyl, or R₁ and R₂ together with their adjacent nitrogen atom form a heterocyclic ring containing 4 to 6 carbon atoms, and where n is 2 or 3, and Y is halogen, preferably chlorine), and then reacted with about one additional equivalent of strong base such as n-BuLi or LDA and about one equivalent of the aldehyde R₃ CHO (where R₃ is as earlier defined). [For further details of this reaction, see Example 2.]

Chromatography

Silica gel chromatography can be used to purify one diastereoisomer of a compound so that it is substantially free of the other. The elution solvent is a mixture of chloroform and methanol in which the methanol has been saturated with ammonia. The usual preferred ratio of chloroform to methanol is 95 to 5 (on a volume basis) but in some cases, alteration in the ratio may improve the chromatographic separation of the diastereoisomers. Where separation is poor, good separation can be achieved by increasing the ratio of silica to compound.

Silica gel chromatography is also useful to separate the compound, as a mixture of diastereoisomers, from impurities.

In the Illustrations and Examples below, chromatography was done by silica gel chromatography using a ratio of chloroform to methanol of 95 to 5.

PREPARATION OF PURE DIASTEREOISOMERS AND PURE ENANTIOMERS

Method F is capable of generating each compound of the invention as a mixture of its two diastereomeric forms. A compound of the invention (when R is H) that exists as a mixture of its two diastereomeric forms may be further purified by silica gel chromatography so that each diastereoisomer exists essentially free of the other diastereoisomer. Purified diastereoisomers of compounds of the invention in which R is lower alkanoyl can be made according to Method G from the corresponding diastereoisomer in which R is H.

Each purified diastereoisomer will be a racemic mixture of two enantiomeric forms. Each purified diastereoisomeric form can be further purified by conventional methods for separating racemic mixtures into its components so that each of its two enantiomeric components exists essentially free of the other. An example of such a method is the reaction of the racemic mixture with a stoichiometric amount of an optically active acid, such as (+)- or (-)- tartaric acid, (+)- or (-)-dibenzoyl tartaric acid, (+)- or (-)-monomethyl tartrate, or other derivative of tartaric acid. The reaction is carried out in a solvent in which the resulting salt of one of the enantiomers of the formula I compound has a different solubility than the resulting salt of the other enantiomer. Methanol, ethanol, or mixtures thereof, are preferred solvents. The preferentially insoluble enantiomer salt is then recovered and converted to the free base by conventional means. If the preferentially insoluble enantiomer salt is still contaminated by an undesirably large amount of the other enantiomer salt, the reaction with tartaric acid or its derivative and the subsequent recovery and conversion steps may be repeated.

PHARMACEUTICAL PREPARATIONS

The compounds of this invention can be employed in the form of pharmaceutical preparations which contain the compound in association with a compatible pharmaceutical carrier. The compounds are thus presented in a form suitable for oral, parenteral or rectal administration, preferably oral. The dosage form may be a solution, suspension, tablet, capsule, or other suitable formulation.

ILLUSTRATIONS OF INTERMEDIATE PREPARATION Illustration 1 Preparation of 4-Dimethylamino-2-phenylbutanenitrile

To a refluxing suspension of 35 g (0.90 mol) of NaNH₂ in 750 ml of toluene was added, dropwise with mechanical stirring under N₂, 100 g (0.85 mol) of phenylacetonitrile in 100 ml of toluene. The resulting suspension was stirred at reflux for a further 3 hr. Then, 92.5 g (0.86 mol) of 2-dimethylaminoethyl chloride in 50 ml of toluene was added dropwise, and the resulting dark suspension was first heated at reflux for 41/2 hr and then stirred at RT for 16 hr. Water (1.5 liters) was added to the mixture, and the organic layer was separated and extracted with 1N HCl. The acid extract was cooled in ice and then basified with 2.5N NaOH. The product was extracted from the basified solution with Et₂ O. The ethereal extract was dried (Na₂ SO₄) and concentrated by evaporation. Distillation of the resulting crude oil afforded 35 g (52.5%) of the desired 4-dimethylamino-2-phenylbutanenitrile as a colorless oil; bp 95°-98°/0.1 mm.

Illustration 2 Preparation of 5-Dimethylamino-2-phenylpentanenitrile

Substitution of an equivalent quantity of 3-(dimethylamino)propyl chloride for 2-(dimethylamino)ethyl chloride in the procedure in Illustration 1 afforded the title compound as a colorless oil, bp 100°-102°/0.1 mm.

Illustration 3 Preparation of Ethyl 4-Dimethylamino-2-phenylbutanoate

10 gms of 4-dimethylamino-2-phenylbutanenitrile dissolved in 200 ml of EtOH saturated with HCl was heated at reflux for 4 hr while bubbling in HCl. The mixture was stirred at RT for 16 hrs and then the solvent was evaporated. The residual oil was dissolved in H₂ O, neutralized with NaHCO₃ and extracted with Et₂ O. The ethereal extracts were combined, dried (Na₂ SO₄), concentrated and distilled to afford 10 gm (80.0%) of ethyl 4-dimethylamino-2-phenylbutanoate as a colorless oil, bp 101°-105°/0.2 mm.

Illustration 4 Preparation of Ethyl 5-Dimethylamino-2-phenylpentanoate

Treatment of 5-dimethylamino-2-phenylpentanenitrile in a fashion similar to the treatment of 4-dimethylamino-2-phenylbutanenitrile in the procedure in Illustration 3 afforded the title compound as a colorless oil, bp 107°-112°/0.2 mm.

Illustration 5 Preparation of N-Methyl-4-dimethylamino-2-phenylbutanamide

To 7.46 g (0.05 mol) of N-methyl phenylacetamide (prepared by reaction of phenylacetyl chloride with monomethylamine in CH₂ Cl₂ solvent) dissolved in 70 ml of THF and cooled in an ice-bath to 0°, was added dropwise with stirring under N₂, 40 ml (0.10 mol) of a 2.5M solution of N-BuLi in n-hexane. After stirring at 0° for 30 min, the solution was treated by the rapid addition of 5.4 g (0.05 mol) of 2-(dimethylamino)ethyl chloride in 30 ml of THF and then stirred at 0° for 30 min. The reaction mixture was then poured into 250 ml of 1N HCl, ether was added and the aqueous layer was separated, basified with 2.5N NaOH and extracted with Et₂ O. The ether extract was dried (Na₂ SO₄), concentrated, and kugelrohr distilled to afford 9.2 g (83.5%) of N-methyl-4-dimethylamino-2-phenylbutanamide as a viscous, colorless oil; bp 130°-135°/0.1 mm.

Following essentially the procedure of Illustration 5 and replacing monomethylamine with

ethylamine,

propylamine, and

isopropylamine,

the following compounds can be made:

N-ethyl-4-dimethylamino-2-phenylbutanamide,

N-propyl-4-dimethylamino-2-phenylbutanamide, and

N-isopropyl-4-dimethylamino-2-phenylbutanamide.

Illustration 6 Preparation of N-Methyl-5-dimethylamino-2-phenylpentanamide

Substitution of an equivalent quantity of 3-(dimethylamino)-propyl chloride for 2-(dimethylamino)ethyl chloride in the procedure in Illustration 5 afforded the title compound as a colorless oil, bp 145°-147°/0.1 mm.

Illustration 7 Preparation of N,N-Dimethyl-4-dimethylamino-2-phenylbutanamide

To a mechanically-stirred, refluxing suspension of 5.85 g (0.15 mol) of NaNH₂ in 150 ml of toluene, was added dropwise under N₂, 50 ml of a toluene solution consisting of 16.3 g (0.1 mol) of N,N-dimethyl-phenylacetamide (prepared by reaction of phenylacetyl chloride and N,N-dimethylamine in CH₂ Cl₂ solvent) in toluene, and the mixture was stirred at reflux for 4 hr. Then, 16.5 g (0.15 mol) of 2-(dimethylamino)ethyl chloride in 100 ml of toluene was added dropwise. The mixture was refluxed for 6 hr and then stirred at RT for 16 hr. Water (150 ml) was added to the mixture, and then the organic layer was separated and extracted with 1N HCl. The acid extract was basified in the cold with 2.5N NaOH and the basic solution extracted with Et₂ O. The ether extract was dried (Na₂ SO₄), concentrated, and distilled to afford 18 g (76.8%) of N,N-dimethyl-4-dimethylamino-2-phenylbutanamide as a colorless oil, bp 108°-110°/0.2 mm.

Following essentially the same procedure of Illustration 7 and replacing phenylacetyl chloride with

4-chlorophenylacetyl chloride,

2-methylphenylacetyl chloride,

4-methoxyphenylacetyl chloride, and

3-nitrophenylacetyl chloride,

the following compounds can be made:

N,N-Dimethyl-4-dimethylamino-2-(4-chlorophenyl)butanamide,

N,N-Dimethyl-4-dimethylamino-2-(2-methylphenyl)butanamide,

N,N-Dimethyl-4-dimethylamino-2-(4-methoxyphenyl)butanamide, and

N,N-Dimethyl-4-dimethylamino-2-(3-nitrophenyl)butanamide.

Following essentially the procedure of Illustration 7 and replacing N,N-dimethylamine by

N,N-diethylamine,

pyrrolidine,

piperidine, and

morpholine,

the following compounds can be made:

N,N-Diethyl-4-dimethylamino-2-phenylbutanamide,

1-[(4-Dimethylamino-1-oxo-2-phenyl)butyl]pyrrolidine,

1-[(4-Dimethylamino-1-oxo-2-phenyl)butyl]piperidine, and

1-[(4-Dimethylamino-1-oxo-2-phenyl)butyl]morpholine.

Following essentially the same procedure, and replacing 2-(dimethylamino)ethyl chloride with the N-protected amino alkyl halides,

2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride,

2-(N-benzyl-N-ethylamino)ethyl chloride, and

2-phthalimidoethyl chloride,

the following compounds can be made:

N,N-dimethyl-4-[N-(benzyloxycarbonyl)-N-methylamino]-2-phenylbutanamide,

N,N-dimethyl-4-[N-benzyl-N-ethylamino]-2-phenylbutanamide, and

N,N-dimethyl-4-phthalimido-2-phenylbutanamide, respectively.

Illustration 8 Preparation of N,N-Dimethyl-5-dimethylamino-2-phenylpentanamide

Substitution of one equivalent quantity of 3-(dimethylamino)propyl chloride for 2-(dimethylamino)ethyl chloride in the procedure in Illustration 7 afforded the title compound as a colorless oil, bp 150°-155°/2.0 mm.

Illustration 9 Preparation of N,N-Dimethyl-4-diisopropylamino-2-phenylbutanamide

Substitution of one equivalent quantity of 2-(diisopropylamino)ethyl chloride for 2-(dimethylamino)ethyl chloride in the procedure in Illustration 7 afforded the title compound as a colorless oil, bp 140°-145°/0.1 mm.

Illustration 10 Preparation of N,N-Dimethyl-5-diisopropylamino-2-phenylpentanamide

Substitution of one equivalent quantity of 3-(diisopropylamino)propyl chloride for 2-(dimethylamino)ethyl chloride in the procedure in Illustration 7 afforded the title compound as a colorless oil, bp 138°-145°/0.1 mm.

Illustration 11 Preparation of N,N-Dimethyl-4-piperidino-2-phenylbutanamide

Substitution of one equivalent quantity of 2-piperidinoethyl chloride for 2-(dimethylamino)ethyl chloride in the procedure in illustration 7 afforded by the title compound as a colorless oil, bp 135°-138°/0.1 mm.

Illustration 12 Preparation of N,N-Dimethyl-5-piperidino-2-phenylpentanamide

Substitution of one equivalent quantity of 3-piperidinopropyl chloride for 2-(dimethylamino)ethyl chloride in the procedure in Illustration 7 afforded by the title compound as a colorless oil, bp 140°-145°/0.1 mm.

Illustration 13 Preparation of N,N-Dimethyl-(2-pyridyl)acetamide

To 5.0 g of ethyl 2-pyridylacetate dissolved in 25 ml of MeOH was added 20 ml of dimethyl amine. The mixture was heated at 90° in a steel autoclave for 96 hrs. The solvent/amine mixture was allowed to evaporate until a residual oil was obtained. The residual oil was distilled to afford 4.5 g of the desired N,N-dimethyl-(2-pyridyl)acetamide as a free-flowing yellow oil, bp 105°-110°/0.5 mm.

Illustration 14 Preparation of N,N-Dimethyl-4-dimethylamino-2-(2-pyridyl)butanamide

Substitution of one equivalent quantity of N,N-dimethyl-(2-pyridyl)acetamide for N,N-dimethylphenylacetamide in the procedure in Illustration 7 afforded the title compound, bp 160°-165°/0.1 mm.

EXAMPLES OF THE PREPARATION OF FORMULA I COMPOUNDS Example 1 Preparation of N,N-Dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide

To a solution of 11.7 g of LDA [prepared from 11.1 g (0.11 mol) of diisopropylamine and 44 ml (0.11 mol) of n-BuLi (2.5M in n-hexane)] in 200 ml of THF, was added at 0° under N₂, 100 ml of a solution of 23.2 g (0.10 mol) of N,N-dimethyl-4-dimethylamino-2-phenylbutanamide in 100 ml of THF, and the resulting solution was stirred at 0° for 30 min. Benzaldehyde (11.7 g, 0.11 mol) in 50 ml of THF was added dropwise over a period of 5 minutes and then the solution was stirred for 5 minutes at 0°. The mixture was poured into 1 liter of ice-cold 1N HCl yielding a colorless solution which was washed with Et₂ O to remove unreacted benzaldehyde, basified by adding 2.5N NaOH while stirring in the cold, and extracted with Et₂ O. The ethereal extract was dried (Na₂ SO₄) and evaporated to afford 30 gm of a yellow oil. Chromatography of the oil afforded 12.0 g of the high r_(f) diastereoisomer of N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, plus 6.0 g of the low r_(f) diastereoisomer.

Dissolution of the high r_(f) diastereoisomer in EtOH, acidification with EtOH/HCl followed by dilution with Et₂ O gave the hydrochloride salt of the high r_(f) diastereoisomer as a colorless powder, mp 210°-211°. [Anal. Calc'd. for C₂₁ H₂₈ N₂ O₂.HCl: C, 66.74; H, 8.00; N, 7.41; Cl, 9.38. Found: C, 66.80; H, 7.99; N, 7.33; Cl, 9.78.]

Treatment of the low r_(f) diastereoisomer in the same manner afforded its hydrochloride salt as a colorless solid, mp 203°-204°. [Anal. Calc'd for C₂₁ H₂₈ N₂ O₂.HCl: C, 66.74; H, 8.00; N, 7.41; Cl, 9.38. Found: C, 66.87; H, 7.91; N, 7.39; Cl, 9.43.]

Following essentially the same procedure, and replacing N,N-dimethyl-4-dimethylamino-2-phenylbutanamide with

N,N-diethyl-4-dimethylamino-2-phenylbutanamide,

1-[(4-dimethylamino-1-oxo-2-phenyl)butyl]pyrrolidine,

1-[(4-dimethylamino-1-oxo-2-phenyl)butyl]piperidine, and

1-[(4-dimethylamino-1-oxo-2-phenyl)butyl]morpholine,

the following compounds can be made:

N,N-diethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide,

1-[[2-(hydroxyphenylmethyl)-4-dimethylamino-1-oxo-2-phenyl]butyl]pyrrolidine,

1-[[2-(hydroxyphenylmethyl)-4-dimethylamino-1-oxo-2-phenyl]butyl]piperidine, and

1-[[2-(hydroxyphenylmethyl)-4-dimethylamino-1-oxo-2-phenyl]butyl]morpholine, respectively.

Following essentially the same procedure, and replacing N,N-dimethyl-4-dimethylamino-2-phenylbutanamide with the (N-protected aminoalkyl) amides,

N,N-dimethyl-4-[N-benzyloxycarbonyl-N-methylamino]-2-phenyl-butanamide,

N,N-dimethyl-4-[N-benzyl-N-ethylamino]-2-phenylbutanamide, and

N,N-dimethyl-4-phthalimido-2-phenylbutanamide,

the following N-protected compounds can be made:

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-(N-benzyloxycarbonyl-N-methylamino)-2-phenylbutanamide,

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-(N-benzyl-N-ethylamino)-2-phenylbutanamide, and

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-phthalimido-2-phenylbutanamide,

respectively, and by using well-known techniques, e.g., hydrogenolysis and hydrazinolysis, the protecting groups are removed to give the following compounds:

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-methylamino-2-phenylbutanamide,

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-ethylamino-2-phenylbutanamide, and

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-amino-2-phenylbutanamide, respectively.

Example 2 Preparation of N-Methyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide

To a solution of 7.46 g (0.05 mol) of N-methylphenylactamide in 70 ml of THF, cooled in an ice-bath to 0°, was added dropwise with stirring under N₂, 40 ml of a 2.5M solution of n-BuLi in n-hexane. The solution was stirred at 0° for 30 min. Then, 5.4 g (0.05 mol) of 2-(dimethylamino)ethyl chloride in 30 ml of THF were added to the solution. The resulting mixture was stirred at 0° for a further 2 hrs. The resulting clear solution was treated with an additional equivalent of n-BuLi (20 ml of 2.5M n-BuLi in n-hexane) and then stirred at 0° for 30 min. A total of 5.3 g (0.05 mol) of benzaldehyde in 20 ml of THF was added to the solution over a 5 min period. The resulting pale, yellow solution was stirred at 0° for an additional 5 min and then poured into 250 ml of ice-cold 1N HCl. The resulting colorless solution was washed with Et₂ O, basified with 2.5N NaOH while stirring in the cold, and extracted with CHCl₃. The CHCl₃ extract was dried (Na₂ SO₄) and evaporated to yield 15 g of a yellow oil. Chromatography of the oil afforded 4.5 g of N-methyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide as a mixture of diastereoisomers, mp 107°-115°. [Anal. Calc'd for C₂₀ H₂₆ N₂ O₂ : C, 73.59; H, 8.03; N, 8.58. Found: C, 73.71; H, 8.13; N, 8.47.]

Example 3 Preparation of N-Methyl-2[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide

To 5.0 g (0.023 mol) of N-methyl-4-dimethylamino-2-phenylbutanamide dissolved in 70 ml of THF, was added with ice-cooling under N₂, 18.1 ml of a 2.5M solutio of n-BuLi in n-hexane, and the resulting solution was stirred at 0° for 30 min. 2-Pyridinecarboxaldehyde (2.42 g, 0.023 mol) dissolved in 20 ml THF was added over a period of 5 min and, after stirring an additional 5 min, the reaction mixture was poured into 150 ml of ice-cold 1N HCl. The resulting clear solution was washed with Et₂ O, basified with 2.5N NaOH while stirring in the cold, and extracted with CHCl₃. The CHCl₃ extract was dried (Na₂ SO₄), and evaporated to afford 4.5 g of a yellow oil. Chromatography of the oil afforded 1.5 g of N-methyl-2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide as a mixture of diastereoisomers. [Anal. Calc'd for C₁₉ H₂₅ N₃ O₂ : C, 69.70; H, 7.70; N, 12.83. Found: C, 69.59; H, 7.73; N, 12.79.]

Following essentially the procedure of Example 3 and replacing N-methyl-4-dimethylamino-2-phenylbutanamide with

N-ethyl-4-dimethylamino-2-phenylbutanamide,

N-propyl-4-dimethylamino-2-phenylbutanamide, and

N-isopropyl-4-dimethylamino-2-phenylbutanamide,

the following compounds can be made:

N-ethyl-2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide,

N-propyl-2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide,

N-isopropyl-2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide.

Example 4 Preparation of 2-[Hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanenitrile

To 9.4 g (0.05 mol) of 4-dimethylamino-2-phenylbutanenitrile dissolved in 100 ml of THF and cooled in an ice bath at 0°, was added dropwise with stirring under N₂, 20 ml of a 2.5M solution of n-BuLi in n-hexane. After stirring at 0° for b 30 min, 5.38 g (0.05 mol) of 2-pyridinecarboxaldehyde in 20 ml THF was added over a period of 5 min and the resulting mixture was stirred for 5 min at 0°. The reaction mixture was then poured into 250 ml of ice-cold 1N HCl and the resulting clear solution was washed with Et₂ O. The ethereal extract was dried (Na₂ SO₄) and evaporated to afford 10 gms of a dark oil. Crystallization of the oil from EtOAc/hexane yielded 6.2 g of 2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanenitrile as a mixture of a diastereoisomers. [Anal. Calc'd for C₁₈ H.sub. 21 N₃ O: C, 73.18; H, 7.17; N, 14.23. Found: C, 72.93; H, 6.86; N, 14.18.]

Example 5 Preparation of Ethyl 2-[Hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanoate

To a solution of 3.0 g of LDA [prepared from 2.85 g (0.028 mol) of diisopropylamine and 11.25 ml of a 2.5M solution of n-BuLi in n-hexane] in 50 ml of THF, was added at 0° under N₂, 5.9 g (0.026 mol) of ethyl 4-dimethylamino-2-phenylbutanoate dissolved in 20 ml of THF, and the resulting solution was stirred at 0° for 30 min. 2-Pyridinecarboxaldehyde (2.7 g, 0.026 mol) dissolved in 10 ml of THF was then added over a period of 5 min and the resulting mixture was stirred at 0° for 5 min. The reaction mixture was then poured into 150 ml of ice-cold 1N HCl and the resulting clear solution was washed with Et₂ O, basified with 2.5N NaOH while stirring in the cold, and extracted with Et₂ O. The ethereal extract was dried (Na₂ SO₄) and evaporated to afford 7.2 g of a yellow oil. Chromatography, yielded 2.5 g of the high r_(f) diastereoisomer of ethyl 2-[hydroxy-(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanoate as an oil and 4.0 g of the corresponding low r_(f) diastereoisomer, also as an oil.

Dissolution of the high r_(f) diastereoisomer in EtOH, acidification with EtOH/HCl followed by Et₂ O gave the hydrochloride salt of the high r_(f) diastereoisomer as a colorless solid, mp 188°-190°. [Anal. Calc'd for C₂₀ H₂₆ N₂ O₃.2HCl: C, 57.83; H, 6.79; N, 6.74; Cl, 17.07. Found: C, 57.81; H, 7.06; N, 6.74; Cl, 17.02.]

Treatment of the low r_(f) diastereoisomer in similar fashion yielded its hydrochloride salt as a colorless solid, mp 205°-207°. [Anal. Calc'd for C₂₀ H₂₆ N₂ O₃.2HCl: C, 57.83; H, 6.79; N, 6.74; Cl., 17.07. Found: 58.14; 7.04; 6.73; 17.01.]

Following essentially the same procedure, and replacing ethyl 4-dimethylamino-2-phenylbutanoate with

ethyl 4-dimethylamino-2-(4-chlorophenyl)butanoate,

ethyl 4-dimethylamino-2-(2-methylphenyl)butanoate,

ethyl 4-dimethylamino-2-(4-methoxyphenyl)butanoate, and

ethyl 4-dimethylamino-2-(3-nitrophenyl)butanoate,

the following compounds can be prepared:

ethyl-2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-(4-chlorophenyl)butanoate,

ethyl 2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-(2-methylphenyl)butanoate,

ethyl 2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-(4-methoxyphenyl)butanoate, and

ethyl 2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-(3-nitrophenyl)butanoate, respectively.

Examples 6-22

In Examples 6-22, substitution of an equivalent quantity of another compound for benzaldehyde, and/or substitution of an equivalent quantity of another compound for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, in the procedure described in Example 1 resulted in the title compound of the Example as a mixture of diastereoisomers.

Example 6 Preparation of N,N-Dimethyl-2-[hydroxy(2-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide

The title compound was produced by substitution of 2-pyridinecarboxaldehyde for benzaldehyde in Example 1. [Anal. Calc'd for C₂₀ H₂₇ N₃ O₂ : C, 70.35; H, 7.97; N, 12.31. Found: C, 69.83; H, 7.82; N, 12.36.]

Example 7 Preparation of N,N-Dimethyl-2-(hydroxycyclohexylmethyl)-4-dimethylamino-2-phenylbutanamide

The title compound was produced by substitution of cyclohexanecarboxaldehyde for benzaldehyde in Example 1. [Anal. Calc'd for C₂₁ H₃₄ N₂ O₂.HCl: C, 65.86; H, 9.21; N, 7.31; Cl, 9.26. Found: C, 65.76; H, 9.30; N, 7.24; Cl, 9.39.]

Example 8 Preparation of N,N-Dimethyl-2-(hydroxyphenylmethyl)-4-diisopropylamino-2-phenylbutanamide

The title compound was produced by substitution of N,N-dimethyl-4-diisopropylamino-2-phenylbutanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide in Example 1. [Anal. Calc'd for C₂₅ H₃₆ N₂ O₂.HCl: C, 69.34; H, 8.61; N, 6.47; Cl, 8.79. Found: C, 69.26; H, 8.46; N, 6.44; Cl, 8.47.]

Example 9 Preparation of N,N-Dimethyl-2-(hydroxyphenylmethyl)-4-piperidino-2-phenylbutanamide

The title compound was produced by substitution of N,N-dimethyl-4-piperidino-2-phenylbutanamide for N,N-dimethyl 4-dimethylamino-2-phenylbutanamide in Example 1. [Anal. Calc'd for C₂₄ H₃₂ N₂ O₂.HCl.1/2H₂ O: C, 67.67; H, 8.04; N, 6.58; Cl, 8.32. Found: C, 67.98; H, 8.02; N, 6.68; Cl, 8.60.]

Example 10 Preparation of N,N-Dimethyl-2-(hydroxyphenylmethyl)-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide in Example 1. [Anal. Calc'd for C₂₂ H₃₀ N₂ O₂.HCl.3/4H₂ O: C, 65.49; H, 7.87; N, 6.94; Cl 8.79. Found: C, 65.21; H, 8.25; N, 6.92; Cl, 9.20.]

Example 11 Preparation of N,N-Dimethyl-2-[hydroxy(2-chlorophenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of 2-chlorobenzaldehyde for benzaldehyde, in Example 1. [Anal. Calc'd for C₂₂ H₂₉ N₂ O₂ Cl.HCl: C, 62.12; H, 7.11; N, 6.59; Cl, 16.67. Found: C, 62.00; H, 7.12; N, 6.37; Cl, 16.46.]

Example 12 Preparation of N,N-Dimethyl-2-[hydroxy(3-chlorophenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of 3-chlorobenzaldehyde for benzaldehyde, in Example 1. [Anal. calc'd for C₂₂ H₂₉ N₂ O₂ Cl.HCl: C, 62.12; H, 7.11; N, 6.59; Cl, 16.67. Found: C, 61.88; H, 7.32; N, 7.32; Cl, 16.40.]

Example 13 Preparation of N,N-Dimethyl-2-[hydroxy(4-chlorophenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of 4-chlorobenzaldehyde for benzaldehyde, in Example 1. [Anal. Calc'd for C₂₂ H₂₉ N₂ O₂ Cl.HCl: C, 61.12; H, 7.11; N, 6.59; Cl, 16.67. Found: C, 62.26; H, 7.06; N, 6.66; Cl, 16.32.]

Example 14 Preparation of N,N-Dimethyl-2-[hydroxy(2,4-dichlorophenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of 2,4-dichlorobenzaldehyde for benzaldehyde, in Example 1. [Anal. Calc'd for C₂₂ H₂₈ N₂ O₂ Cl₂.HCl: C, 57.46; H, 6.36; N, 6.09; Cl, 23.13. Found: C, 57.61; H, 6.25; N, 6.08; Cl, 23.36.]

Example 15 Preparation of N,N-Dimethyl-2-[hydroxy(2-bromophenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of 2-bromobenzaldehyde for benzaldehyde, in Example 1. [Anal. Calc'd for C₂₂ H₂₉ N₂ O₂ Br.HBr: C, 51.38; H, 5.88; N, 5.45; Br, 31.07. Found: C, 51.04; H, 5.98; N, 5.36; Br, 30.84.]

Example 16 Preparation of N,N-Dimethyl-2-[hydroxy(4-methoxyphenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of p-anisaldehyde for benzaldehyde in Example 1. [Anal. Calc'd for C₂₃ H₃₂ N₂ O₃.HCl: C, 65.62; H, 7.90; N, 6.65; Cl, 8.42. Found: C, 65.58; H, 7.99; N, 6.62; Cl, 8.55.]

Example 17 Preparation of N,N-Dimethyl-2-[hydroxy(2-methylphenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of o-tolualdehyde for benzaldehyde, Example 1. [Anal. Calc'd for C₂₃ H₃₂ N₂ O₂.HCl.3/4H₂ O; C, 66.01; H, 8.31; N, 6.69; Cl, 8.47. Found: C, 66.24; H, 8.02; N, 6.68; Cl, 9.04.]

Example 18 Preparation of N,N-Dimethyl-2-[hydroxy(4-methylphenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of p-tolualdehyde for benzaldehyde, Example 1. [Anal. Calc'd for C₂₃ H₃₂ N₂ O₂.HCl: C, 68.21; H, 8.21; N, 6.92; Cl, 8.75. Found: C, 68.32; H, 8.23; N, 6.94; Cl, 8.88.]

Example 19 Preparation of N,N-Dimethyl-2-[hydroxy(3-nitrophenyl)methyl]-5-dimethylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-dimethylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide, as well as substitution of 3-nitrobenzaldehyde for benzaldehyde, in Example 1. [Anal. Calc'd for C₂₂ H₂₉ N₃ O₄.HCl: C, 60.61; H, 6.94; N, 9.64; Cl, 8.13. Found: C, 60.16; H, 7.07; N, 9.50; Cl, 8.50.]

Example 20 Preparation of N,N-Dimethyl-2-(hydroxyphenylmethyl)-5-diisopropylamino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-diisopropylamino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide in Example 1. [Anal. Calc'd for C₂₆ H₃₈ N₂ O₂.HCl: C, 69.85; H, 8.79; N, 6.27; Cl, 7.92. Found: C, 69.83; H, 8.87; N, 6.10; Cl, 8.03.]

Example 21 Preparation of N,N-Dimethyl-2-(hydroxyphenylmethyl)-5-piperidino-2-phenylpentanamide

The title compound was produced by substitution of N,N-dimethyl-5-piperidino-2-phenylpentanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide in Example 1. [Anal. Calc'd for C₂₅ H₃₈ N₂ O.HCl.3/4H₂ O: C, 69.42; H, 9.44; N, 6.48; Cl, 8.20. Found: C, 68.28; H, 8.36; N, 6.34; U, 8.40.]

Example 22 Preparation of N,N-Dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-(2-pyridyl)-butanamide

The title compound was produced by substitution of N,N-dimethyl-4-dimethylamino-2-(2-pyridyl)-butanamide for N,N-dimethyl-4-dimethylamino-2-phenylbutanamide in Example 1. [Anal. Calc'd for C₂₀ H₂₇ N₃ O₂ : Cl, 70.35; H, 7.97; N, 12.43. Found: C, 70.16; H, 8.22; N, 12.43.]

Following essentially the procedure of Example 1, and replacing N,N-dimethyl-4-dimethylamino-2-phenylbutanamide with

N,N-dimethyl-4-dimethylamino-2-(4-chlorophenyl)butanamide,

N,N-dimethyl-4-dimethylamino-2-(2-methylphenyl)butanamide,

N,N-dimethyl-4-dimethylamino-2-(4-methoxyphenyl)butanamide, and

N,N-dimethyl-4-dimethylamino-2-(3-nitrophenyl)butanamide,

the following compounds can be made:

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-(4-chlorophenyl)butanamide,

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-(2-methylphenyl)butanamide

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-(4-methoxyphenyl)butanamide, and

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-(3-nitrophenyl)butanamide, respectively.

Following essentially the procedure of Example 1 and replacing N,N-dimethyl-4-dimethylamino-2-phenylbutanamide with

N,N-dimethyl-4-cyclohexylamino-2-phenylbutanamide,

N,N-dimethyl-5-cyclohexylamino-2-phenylpentanamide,

N,N-dimethyl-4-cyclopropylamino-2-phenylbutanamide, and

N,N-dimethyl-5-cyclopropylamino-2-phenylpentanamide,

the following compounds can be made:

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-cyclohexylamino-2-phenylbutanamide,

N,N-dimethyl-2-(hydroxyphenylmethyl)-5-cyclohexylamino-2-phenylpentamide,

N,N-dimethyl-2-(hydroxyphenylmethyl)-4-cyclopropylamino-2-phenylbutanamide, and

N,N-dimethyl-2-(hydroxyphenylmethyl)-5-cyclopropylamino-2-phenylpentamide, respectively.

Example 23 Preparation of N-Methyl-2-(hydroxyphenylmethyl)-5-dimethylamino-2-phenylpentanamide

To N-methyl-5-dimethylamino-2-phenylpentanamide (5.0 g, 0.023 mol) dissolved in 50 ml THF was added 18.1 ml of a 2.5M solution of n-BuLi in n-hexane with ice-cooling under N₂. After stirring at 0° C. for 30 min, benzaldehyde (2.4 g, 0.023 mol) dissolved in 10 ml THF was added dropwise to the foregoing solution. The reaction mixture was stirred for 5 min at 0° C. and then poured into ice-cold HCl. The resulting solution was washed with Et₂ O, basified by adding dilute NaOH while stirring in the cold, and extracted with CHCl₃. The CHCl₃ extracts were combined, dried (Na₂ SO₄), and evaporated. Chromatography of the post-evaporation residue afforded the desired compound as a mixture of diastereoisomers as an oil. Dissolution in EtOH, acidification with HCl, followed by addition of Et₂ O gave the hydrochloride salt as a colorless solid. [Anal. Calc'd for C₂₁ H₂₈ N₂ O₂.HCl1/4EtOH: C, 66.17; H, 7.93; N, 7.18; Cl, 9.08. Found: C, 65.82; H, 8.02; N, 7.04; Cl 10.27.]

Example 24 Preparation of 2-(Hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanenitrile

Substitution of one equivalent quantity of benzaldehyde for 2-pyridinecarboxaldehyde in the procedure of Example 4 afforded the title compound as a mixture of diastereoisomers. [Anal. Calc'd for C₁₉ H₂₂ N₂ O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.27; H, 7.45; N, 9.59.]

Example 25 Preparation of 2-(Hydroxyphenylmethyl)-5-dimethylamino-2-phenylpentanenitrile

Substitution of one equivalent quantity of 5-dimethylamino-2-phenylpentanenitrile for 4-dimethylamino-2-phenylbutanenitrile and one equivalent quantity of benzaldehyde for 2-pyridinecarboxaldehyde in the procedure of Example 4 afforded the title compound as a mixture of diastereoisomers. [Anal. Calc'd for C₂₀ H₂₄ N₂ O: C, 77.89; H, 7.84; N, 9.08. Found: C, 76.58; H, 7.90; N, 8.94.]

Example 26 Preparation of 2-[Hydroxy(2-pyridyl)methyl]-5-dimethylamino-2-phenylpentanenitrile

Substitution of one equivalent quantity of 5-dimethylamino-2-phenylpentanenitrile for 4-dimethylamino-2-phenylbutanenitrile in the procedure of Example 4 afforded the title compound as a mixture of diastereoisomers. [Anal. Calc'd for C₁₉ H₂₃ N₃ O: C, 73.76; H, 7.49; N, 13.58. Found: C, 73.69; H, 7.55; N, 13.69.]

Example 27 Preparation of Ethyl 2-(Hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanoate

Substitution of one equivalent quantity of benzaldehyde for 2-pyridinecarboxaldehyde in the procedure in Example 5 afforded the individual diastereoisomers of the title compound: high r_(f) diastereoisomer (mp 113°-115° C.); low r_(f) diastereoisomer (mp 72°-74° C.).

Example 28 Preparation of Ethyl 2-(Hydroxyphenylmethyl)-5-dimethylamino-2-phenylpentanoate

Substitution of one equivalent quantity of ethyl 5-dimethylamino-2-phenylpentanoate for 4-dimethylamino-2-phenylbutanoate and benzaldehyde for 2-pyridinecarboxaldehyde in the procedure in Example 5 afforded the individual diastereoisomers of the title compound: high r_(f) diastereoisomer (mp 113°-115° ), low diastereoisomer (mp 91°-93° C.).

Example 29 Preparation of N,N-Dimethyl-2-[hydroxy-(4-methoxyphenyl)methyl]-4-dimethylamino-2-phenylbutanamide

The title compound was produced by substitution of p-anisaldehyde for benzaldehyde in Example 1. The chromatography step led to the isolation of the pure diastereoisomers as free bases. Treatment of the free bases with EtOH/HCl afforded the solid HCl salts: (high r_(f) diastereoisomer, mp 205°-207° C.; low r_(f) diastereoisomer, mp 175°-176° C.).

Example 30 Preparation of N,N-Dimethyl-2[(acetyloxy-phenylmethyl]-4-dimethylamino-2-phenylbutanamide, High melting point diastereoisomer

To 9.0 g (0.026 mol) of N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, high r_(f) diastereoisomer, dissolved in 150 ml of dry pyridine, was added 7.4 g (0.071 mol) of acetic anhydride, and the clear solution was stirred at RT under N₂ for 40 hours. The solvent was then evaporated off at reduced pressure and the remaining oil partitioned between CHCl₃ and aq. NaHCO₃. The CHCl₃ extract was dried and evaporated to afford the product as a light yellow oil. Dissolution in ETOH and acidification with ETOH/HCl followed by addition of ether in the cold gave the hydrochloride salt of the title compound, as a colorless solid; yield 8.3 g (76.2%), mp 280° (dec).

Example 31 Preparation of N,N-Dimethyl-2-[(acetyloxy)phenylmethyl]-4-dimethylamino-2-phenylbutanamide, Low melting point diastereoisomer

Substitution of one equivalent quantity of N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, low r_(f) diastereoisomer for N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, high r_(f) diastereoisomer, in the procedure of Example 30 afforded the title compound as its hydrochloride salt. (mp 230°-232° ).

Example 32 Preparation of N,N-Dimethyl-2-[(acetyloxy)(4-methoxyphenyl)methyl]-4-dimethylamino-2-phenylbutanamide, High melting point diastereoisomer

Substitution of one equivalent quantity of N,N-dimethyl-2-[hydroxy-(4-methoxyphenyl)methyl]-4-dimethylamino-2-phenylbutanamide, high r_(f) diastereoisomer, for N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, high r_(f) diastereoisomer, in the procedure of Example 30 afforded the title compound as its hydrochloride salt. (mp 248°-253°).

Example 33 Preparation of N,N-Dimethyl-2-[(acetyloxy)(4-methoxyphenyl)methyl]-4-dimethylamino-2-phenylbutanamide, Low melting point diastereoisomer

Substitution of one equivalent quantity of N,N-dimethyl-2-[hydroxy(4-methoxyphenyl)methyl]-4-dimethylamino-2-phenylbutanamide, low r_(f) diastereoisomer, for N,N-dimethyl-2-(hydroxyphenylmethyl)-4-dimethylamino-2-phenylbutanamide, high r_(f) diastereoisomer, in the procedure of Example 30 afforded the title compound as the hydrochloride salt. (mp 220°-223°).

Example 34 Preparation of N,N-Dimethyl-2-[hydroxy(3-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide

The title compound was produced by substitution of 3-pyridinecarboxaldehyde for benzaldehyde in Example 1. [Anal. Calc'd for C₂₀ H₂₇ N₃ O₂ : C, 70.35; H, 7.97; N, 12.31. Found: C, 70.23; H, 8.03; N, 2.25]

Example 35 Preparation of N,N-Dimethyl-2-[hydroxy(4-pyridyl)methyl]-4-dimethylamino-2-phenylbutanamide

The title compound was produced by substitution of 4-pyridinecarboxaldehyde for benzaldehyde in Example 1. [Anal. Calc'd for C₂₀ H₂₇ N₃ O₂.2HCl.1/2H₂ O.C, 56.74; H, 7.14; N, 9.92; Cl, 16.75. Found: C, 55.84; H, 6.94; N, 9.76; Cl, 17.57]

Example 36 Preparation of N,N-Dimethyl-3-hydroxy-2-dimethylaminoethyl-2-phenylpentanamide

The title compound was produced by substitution of propionaldehyde for benzaldehyde in Example 1. [Anal. Calc'd C₁₇ H₂₈ N₂ O₂.HCl: C, 62.09; H, 8.89; N, 8.52; Cl, 10.78. Found C, 61.53; H, 8.97; N, 8.60; l, 10.95] 

What is claimed is:
 1. A compound of the formula ##STR5## wherein R is hydrogen or lower alkanoyl,R₁ and R₂ are independently hydrogen, lower alkyl or lower cycloalkyl, or R₁ and R₂ together with their adjacent nitrogen atom form a heterocyclic ring selected from the group of pyrrolidino, piperidino, morpholino, piperazino and 1H-hexahydroazepino; R₃ is phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or lower cycloalkyl; Ar is phenyl, substituted phenyl, or 2-pyridyl; X is CO₂ R₄, or CONR₅ R₆ ; R₄ is hydrogen or lower alkyl; R₅ and R₆ are independently hydrogen or lower alkyl, or R₅ and R₆ together with their adjacent nitrogen atom form a heterocyclic ring selected from the group of pyrrolidino, piperidino, morpholino, piperazino and 1H-hexahydroazepino; substituted phenyl is phenyl that is either monosubstituted or disubstituted and each substituent is selected from the group consisting of halogen, lower alkyl, lower alkoxy, amino, nitro, or hydroxy, such that substitution can occur at the ortho, meta or para positions; and n is 2 or 3, including all enantiomers thereof and mixtures of enantiomers thereof.
 2. A compound of claim 1 wherein R₃ is phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
 3. The compound of claim 1 wherein R is hydrogen or acetyl; R₁ and R₂ are either both CH₃, both isopropyl, or together with their adjacent N form piperidino; Ar is phenyl; and X is CO₂ C₂ H₅, CONHCH₃, or CON(CH₃)₂.
 4. The compound as defined in claim 1 wherein R₁ and R₂ are both CH₃, R₃ is phenyl, R is hydrogen, Ar is phenyl, X is CON(CH₃)₂ and n is
 2. 5. The compound as defined in claim 1 wherein R₁ and R₂ are both CH₃, R₃ is phenyl, R is hydrogen, Ar is phenyl, X is CON(CH₃)₂ and n is
 3. 6. The compound as defined in claim 1 wherein R₁ and R₂ are both CH₃, R₃ is 2-pyridyl, R is hydrogen, Ar is phenyl, X is CO₂ C₂ H₅ and n is
 2. 7. The compound as defined in claim 1 wherein R₁ and R₂ are both CH₃, R₃ is phenyl, R is hydrogen, Ar is phenyl, X is CO₂ C₂ H₅ and n is
 3. 8. The compound as defined in claim 1 wherein R₁ and R₂ are both isopropyl, R₃ is phenyl, R is hydrogen, Ar is phenyl, X is CON(CH₃)₂ and n is
 2. 9. The compound as defined in claim 1 wherein R₁ and R₂ are methyl, R₃ is 4-methoxyphenyl, R is hydrogen, Ar is phenyl, X is CON(CH₃)₂ and n is
 2. 10. The compound of claim 1 wherein R is acetyl, R₁ and R₂ are methyl, Ar is phenyl, R₃ is phenyl, X is CON(CH₃)₂ and n is
 2. 11. The compound of claim 1 wherein R is acetyl, R₁ and R₂ are methyl, Ar is phenyl, R₃ is 4-methoxyphenyl, X is CON(CH₃)₂ and n is
 2. 12. The compound of claim 1 wherein R is hydrogen, R₁ and R₂ together with their adjacent nitrogen atom form piperidino, Ar is phenyl, R₃ is phenyl, X is CON(CH₃)₂ and n is
 2. 13. The compound of claim 1 wherein R is hydrogen, R₁ and R₂ are isopropyl, Ar is phenyl, R₃ is phenyl, X is CON(CH₃)₂ and n is
 3. 14. The compound of claim 1 wherein R is hydrogen, R₁ and R₂ together with their adjacent nitrogen atom form piperidino, Ar is phenyl, R₃ is phenyl, X is CON(CH₃)₂ and n is
 3. 15. The high r_(f) diastereoisomer of the compound defined in claim
 4. 16. The low r_(f) diastereoisomer of the compound defined in claim
 4. 17. The high r_(f) diastereoisomer of the compound defined in claim
 6. 18. The low r_(f) diastereoisomer of the compound defined in claim
 6. 19. The high r_(f) diastereoisomer of the compound defined in claim
 7. 20. The low r_(f) diastereoisomer of the compound defined in claim
 7. 21. The high melting point diastereoisomer of the compound defined in claim
 10. 22. The low melting point diastereoisomer of the compound defined in claim
 10. 23. The high melting point diastereoisomer of the compound defined in claim
 11. 24. The low melting point diastereoisomer of the compound defined in claim
 11. 